Background

Activities of hepatic cytochrome P450 enzymes (CYPs) are relevant for hepatic clearance of drugs and known to be decreased in patients with liver cirrhosis. Several studies have reported the effect of liver cirrhosis on CYP activity, but the results are partially conflicting and for some CYPs lacking.

Objective

In this study, we aimed to investigate the CYP activity in patients with liver cirrhosis with different Child stages (A-C) using the Basel phenotyping cocktail approach.

Methods

We assessed the pharmacokinetics of the six compounds and their CYP-specific metabolites of the Basel phenotyping cocktail (CYP1A2: caffeine, CYP2B6: efavirenz, CYP2C9: flurbiprofen, CYP2C19: omeprazole, CYP2D6: metoprolol, CYP3A: midazolam) in patients with liver cirrhosis (n = 16 Child A cirrhosis, n = 15 Child B cirrhosis, n = 5 Child C cirrhosis) and matched control subjects (n = 12).

Results

While liver cirrhosis only marginally affected the pharmacokinetics of the low to moderate extraction drugs efavirenz and flurbiprofen, the elimination rate of caffeine was reduced by 51% in patients with Child C cirrhosis. For the moderate to high extraction drugs omeprazole, metoprolol, and midazolam, liver cirrhosis decreased the elimination rate by 75%, 37%, and 60%, respectively, increased exposure, and decreased the apparent systemic clearance (clearance/bioavailability). In patients with Child C cirrhosis, the metabolic ratio (ratio of the area under the plasma concentration–time curve from 0 to 24 h of the metabolite to the parent compound), a marker for CYP activity, decreased by 66%, 47%, 92%, 73%, and 43% for paraxanthine/caffeine (CYP1A2), 8-hydroxyefavirenz/efavirenz (CYP2B6), 5-hydroxyomeprazole/omeprazole (CYP2C19), α-hydroxymetoprolol/metoprolol (CYP2D6), and 1′-hydroxymidazolam/midazolam (CYP3A), respectively. In comparison, the metabolic ratio 4-hydroxyflurbiprofen/flurbiprofen (CYP2C9) remained unchanged.

Conclusions

Liver cirrhosis affects the activity of CYP isoforms differently. This variability must be considered for dose adjustment of drugs in patients with liver cirrhosis.

Clinical Trial Registration

NCT03337945.

中文翻译：

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肝硬化对巴塞尔表型鸡尾酒六种底物的药代动力学有不同的影响

背景

肝细胞色素 P450 酶 (CYP) 的活性与药物的肝脏清除有关，已知在肝硬化患者中会降低。几项研究报告了肝硬化对 CYP 活性的影响，但结果部分相互矛盾，并且某些 CYP 缺乏。

客观的

在这项研究中，我们旨在使用巴塞尔表型鸡尾酒方法研究不同儿童阶段 (AC) 肝硬化患者的 CYP 活性。

方法

我们评估了六种化合物及其 CYP 特异性代谢物的巴塞尔表型鸡尾酒（CYP1A2：咖啡因，CYP2B6：依非韦伦，CYP2C9：氟比洛芬，CYP2C19：奥美拉唑，CYP2D6：美托洛尔，CYP3A：咪达唑仑）在肝硬化患者中的药代动力学（n = 16 名儿童 A 肝硬化，n = 15 名儿童 B 肝硬化，n = 5 名儿童 C 肝硬化）和匹配的对照受试者（n = 12）。

结果

虽然肝硬化对低至中度提取药物依非韦伦和氟比洛芬的药代动力学影响很小，但 Child C 肝硬化患者的咖啡因消除率降低了 51%。对于中高提取药物奥美拉唑、美托洛尔和咪达唑仑，肝硬化的消除率分别降低了75%、37%和60%，暴露量增加，表观全身清除率（清除率/生物利用度）降低。在 Child C 型肝硬化患者中，CYP 活性标志物的代谢比（代谢物 0 到 24 小时血浆浓度-时间曲线下面积与母体化合物的比值）下降了 66%、47%、对黄嘌呤/咖啡因 (CYP1A2)、8-羟基依法韦仑/依法韦仑 (CYP2B6)、5-羟基奥美拉唑/奥美拉唑 (CYP2C19) 分别为 92%、73% 和 43%，分别为 α-羟基美托洛尔/美托洛尔 (CYP2D6) 和 1'-羟基咪达唑仑/咪达唑仑 (CYP3A)。相比之下，代谢比 4-羟基氟比洛芬/氟比洛芬 (CYP2C9) 保持不变。

结论

肝硬化对 CYP 亚型的活性有不同的影响。对于肝硬化患者的药物剂量调整，必须考虑这种可变性。

临床试验注册

NCT03337945。